The long-term objective is to understand mechanisms of estrogen action in the male reproductive tract and to relate estrogen receptor dysfunction to human male infertility associated with oligospermia and sperm granulomas in the head of the epididymis. Estrogen receptor-alpha (ER) is essential for normal growth of the male reproductive tract and ER dysfunction in the ER knockout mouse (ERKO) causes infertility. The efferent ducts of the ERKO mouse do not reabsorb fluid, which causes fluid to back up into the testis and subsequently induces testicular atrophy. In human, mutational dysfunction in ER-alpha and P450 aromatase (which converts and androgens to estrogens) decreases sperm counts and results in poor sperm viability. Tamoxifen, which is commonly known to be a mixed estrogen agonist/antagonist in different tissues, has been used clinically to increase sperm counts in oligospermic men. The proposed experiments will test the hypothesis that estrogen stimulates fluid reabsorption in efferent ducts by altering either Cr secretion or Na+ transport or both. Specific aims are: a) to measure the magnitude of fluid reabsorption regulated by estrogen in efferent ducts and initial segment epididymidis in normal, antiestrogen-treated and ERKO mice; b) to measure the concentrations of Na+, K+, and CI- and osmotic pressure in luminal fluids in the three treatment groups: and c) to compare micropuncture data with electrophysiological alterations in NaCI absorption in vitro in the ERKO efferent ductal epithelium and in cultured ductal epithelium treated with the antiestorgen. The proposed research is fundamental to the understanding of estrogen and male infertility.